THIS IS A SHANNON AWARD PROVIDING PARTIAL SUPPORT FOR THE RESEARCH PROJECTS THAT FALL SHORT OF THE ASSIGNED INSTITUTE'S FUNDING RANGE BUT ARE IN THE MARGIN OF EXCELLENCE. THE SHANNON AWARD IS INTENDED TO PROVIDE SUPPORT TO TEST THE FEASIBILITY OF THE APPROACH; DEVELOP FURTHER TESTS AND REFINE RESEARCH TECHNIQUES; PERFORM SECONDARY ANALYSIS OF AVAILABLE DATA SETS; OR CONDUCT DISCRETE PROJECTS THAT CAN DEMONSTRATE THE PI'S RESEARCH CAPABILITIES OR LEAD ADDITIONAL WEIGHT TO AN ALREADY MERITORIOUS APPLICATION. THE APPLICATION BELOW IS TAKEN FROM THE ORIGINAL DOCUMENT SUBMITTED BY THE PRINCIPAL INVESTIGATOR. Cholelithiasis or the formation of gallstones is a human disease that accounts for almost 1% of health care costs or 8 billion dollars annually. Gallstone formation is familial but very little is known about the genetic basis of this disease. Using inbred strains of mice, we recently demonstrated that gallstone formation was genetically determined and that two major genes, which we named Lith1 and Lith2, account for most of difference in gallstone susceptibility between strains C57L and AKR. We propose to continue these studies of the genetic basis of gallstone formation by developing the mouse as a model for cholelithiasis, because no other mammalian species currently used as an experimental model for cholelithiasis has the genetic tools that are available in the mouse. In this proposal, we will map Lith1 and Lith2 with greater precision, aiming for a resolution of about 0.1 cM. In addition we will carry out crosses of two other gallstone-susceptible strains, SWR and A, with the gallstone-resistant strain AKR to determine if the same genes determine gallstone susceptibility in these strains or whether other genes are involved. Identifying all possible genes in the mouse that affect gallstone formation will aid in the search for gallstone genes in humans. Gallstone-resistant stains of mice downregulate HMG CoA reductase activity in the liver when fed a high cholesterol diet, but gallstone- susceptible strains fail to do so. We will determine whether the regulation of HMG CoA reductase activity is the key biochemical difference underlying gallstone susceptibility and at which step the regulation occurs. We will also construct reciprocal congenic strains of Lith1 and Lith2 so that the pathophysiology of cholelithiasis and the impact of Lith1 and Lith2 in the process can be studied more precisely.